Candidate: The applicant is an associate professor of Neurology at the university of Maryland and a staff neurologist at the Baltimore VA Medical Center. Current academic activities include clinical and basic research in multiple sclerosis (MS). Currently, there are two ongoing research projects in the applicant's laboratory: The first is a VA funded Merit Review Award through March, 2002 to examine mechanisms of virus persistence in human neurons, and the second is to examine the therapeutic mechanisms of 2 newly approved drugs for MS, IFNbeta and copolymer-1. During the past 6-years four postdoctoral fellows conducted research related to MS in the applicant's laboratory. Environment: The Maryland Center for MS is internationally recognized for clinical and basic research in MS. Clinical research at this center contributed to the FDA approval of 2 of the 3 currently marketed drugs for MS namely Betaseron and copolymer-1. More than 800 annual patient visits occur, and the center participates in several multisite clinical trials. The center is staffed by 5 full time MS specialists, 3 nurses, and 2 support staff. Research: The proposed research will focus on understanding the therapeutic mechanisms of Betaseron and copolymer-1 in MS. Supplies and partial technical support for this research is currently provided by Berlex and TEVA, the manufacturers of Betaseron and copolymer-1 respectively. Our specific aims include: 1. Examination of the modulatory effect of IFNbeta treatment on IL-12 in MS. IL-12 is a pro-inflammatory cytokine implicated in the pathogenesis of MS. Preliminary data indicate that IFNbeta has a cell-specific regulatory effect on IL-12 in peripheral blood mononuclear cells (PBMNC). We will examine the mechanism of this regulatory effect both in vitro and ex-vivo using PBMNC from MS patients pre- and post-treatment with IFNbeta. The findings will also be correlated with MRI disease activity. 2. Mechanisms of Copolymer-I therapy in MS. We will examine the immunologic effects of copolymer-1 in PBMNC obtained ex-vivo from MS patients treated with this drug. This includes induction of copolymer-1 specific regulatory cells, whether these cells cross react with myelin antigens and induce cytokine deviation, or whether copolymer-1 produces T-cell anergy. The proposed research could help identify components of the immunologic network in MS that are associated with response to treatment, and therefore help in the design of more effective future therapies.